US 12,275,727 B2
Compound containing structure of a five-membered heteroaromatic ring, pharmaceutical compositions thereof and applications thereof
Zusheng Xu, Shanghai (CN); Yangtong Lou, Shanghai (CN); Tiegang Xie, Shanghai (CN); Linlin Xu, Shanghai (CN); Li Chen, Shanghai (CN); Yanhang Liu, Shanghai (CN); and Qingrui Sun, Shanghai (CN)
Assigned to 280 BIO, INC., South San Francisco, CA (US)
Filed by 280 Bio, Inc., South San Francisco, CA (US)
Filed on Mar. 6, 2023, as Appl. No. 18/178,668.
Claims priority of application No. 202210214607.4 (CN), filed on Mar. 4, 2022; application No. 202210831127.2 (CN), filed on Jul. 15, 2022; and application No. 202211288698.2 (CN), filed on Oct. 20, 2022.
Prior Publication US 2023/0278998 A1, Sep. 7, 2023
Int. Cl. C07D 417/14 (2006.01); C07D 417/04 (2006.01); C07D 471/04 (2006.01); C07D 487/08 (2006.01)
CPC C07D 417/14 (2013.01) [C07D 417/04 (2013.01); C07D 471/04 (2013.01); C07D 487/08 (2013.01)] 13 Claims
 
1. A compound containing structure of a five-membered heteroaromatic ring represented by formula II, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

OG Complex Work Unit Chemistry
wherein, custom character represents a single bond or a double bond;

OG Complex Work Unit Chemistry
both rings of are aromatic;
Ra1, Ra2 and Ra3 are independently hydrogen, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —ORa-1, C(═O) Ra-2, —NRa-31Ra-32, —C(═O)ORa-4, —C(═O)NRa-51Ra-52, or, C1-6 alkyl substituted with one or more Ra1-1, Ra1-1 is halogen, hydroxyl or —OC1-6 alkyl;
or, Ra2 and Ra3, together with the carbon atom to which they are attached form C3-7 cycloalkane, C3-7 cycloalkane substituted with one or more Ra2-1, “3- to 8-membered heterocycloalkyl containing 1 to 3 hetroatoms independently selected from O, S and N”, “3- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more Ra2-2; provided that when multiple substituents are present, the substituents are the same or different;
Ra2-1 and Ra2-2 are independently halogen, oxo, hydroxyl, C1-6 alkyl, or C1-6 alkyl substituted with one or more halogen, —OC1-6 alkyl, and —OC1-6 alkyl substituted with one or more halogen;
Ra-1, Ra-2, Ra-31, Ra-32, Ra-4, Ra-51 and Ra-52 are independently hydrogen, C1-6 alkyl, or, C1-6 alkyl substituted with one or more halogens;
A1 is CR1;
R1 is hydrogen, cyano, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl, C1-6 alkyl substituted with one or more R1-1, halogen, hydroxyl, —OC1-6 alkyl, —OC1-6 alkyl substituted with one or more R1-2, —C(═O) R1a, —NR1b1R1b2, —C(═O)OR1c, —C(═O)NR1d1R1d2, C3-10 cycloalkyl, C3-10 cycloalkyl substituted with one or more R1-3, “4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N”, “4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more R1-4, C6-20 aryl, C6-20 aryl substituted with one or more R1-5, “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N”, “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N” substituted with one or more R1-6, C5-7 cycloalkenyl, C5-7 cycloalkenyl substituted with one or more R1-7, “5-to 7-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from O, S and N”, “5- to 7-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more R1-8, or, C2-6 alkynyl substituted with one or more R1-9; provided that when multiple substituents are present, the substituents are the same or different;
R1-1, R1-2, R1-3, R1-4, R1-5, R1-6, R1-7, R1-8 and R1-9 are independently azide, halogen, hydroxyl, cyano, oxo, C1-6 alkyl, C1-6 alkyl substituted with one or more R1-1-1, C2-6 alkenyl, C2-6 alkynyl, —OC1-6 alkyl, —OC1-6 alkyl substituted with one or more R1-1-2, —C(═O) R11a, —NR11b1R11b2, —C(═O)OR11c, —C(═O)NR11d1R11d2, —S(O)2NR11e1, R11e2, —S(O)2R11f, C3-10 cycloalkyl, C3-10 cycloalkyl substituted with one or more R1-1-3, “4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N”, “4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more R1-1-4, C6-20 aryl, C6-20 aryl substituted with one or more R1-1-5, “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N”, “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N” substituted with one or more R1-1-6, C5-7 cycloalkenyl, C5-7 cycloalkenyl substituted with one or more R1-1-7, “5- to 7-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from O, S and N”, “5- to 7-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more R1-1-8, provided that when multiple substituents are present, the substituents are the same or different;
R1-1-1, R1-1-2, R1-1-3, R1-1-4, R1-1-5, R1-1-6, R1-1-7 and R1-1-8 are independently halogen, —C(═O) R11g, hydroxyl, oxo, C1-6 alkyl, or, C1-6 alkyl substituted with one or more R1-1-1-1; provided that when multiple substituents are present, the substituents are the same or different;
R1-1-1-1 is halogen, hydroxyl, —OC1-6 alky or —NRaRb, Ra and Rb are independently hydrogen or C1-6 alkyl;
R1a, R1b1, R1b2, R1c, R1d1, R1d2, R11a, R11b1, R11b2, R11c, R11d1, R11d2, R11e1, R11e2, R11f and R11g are independently hydrogen, C1-6 alkyl, C1-6 alkyl substituted with one or more R1-2-1, —OC1-6 alkyl, —OC1-6 alkyl substituted with one or more R1-2-2, C3-10 cycloalkyl, C3-10 cycloalkyl substituted with one or more R1-2-3, “4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N”, “4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more R1-2-4, C6-20 aryl, C6-20 aryl substituted with one or more R1-2-5, “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N”, “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N” substituted with one or more R1-2-6, C5-7 cycloalkenyl, C5-7 cycloalkenyl substituted with one or more R1-2-7, “5- to 7-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from O, S and N”, “5- to 7-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more R1-2-8 or, —C(═O) R11h; R11h is C1-6 alky; provided that when multiple substituents are present, the substituents are the same or different; R1-2-1, R1-2-2, R1-2-3, R1-2-4, R1-2-5, R1-2-6, R1-2-7 and R1-2-8 are independently halogen, hydroxyl, —NR12cR12d, oxo, C1-6 alkyl, C1-6 alkyl substituted with one or more R1-2-1-1, R12c and R12d are independently hydrogen or C1-6 alkyl; provided that when multiple substituents are present, the substituents are the same or different;
R1-2-1-1 is independently halogen, hydroxyl, —OC1-6 alkyl or —NRcRd, Rc and Rd are independently hydrogen or C1-6 alkyl;
or, when the number of R1-3, R1-4, R1-5, R1-6, R1-7, R1-8, R1-1-3, R1-1-4, R1-1-5, R1-1-6, R1-1-7, R1-1-8, R1-2-3, R1-2-4, R1-2-5, R1-2-6, R1-2-7 or R1-2-8 is more than one, two optional R1-3, two optional R1-4, two optional R1-5, two optional R1-6, two optional R1-7, two optional R1-8, two optional R1-1-3, two optional R1-1-4, two optional R1-1-5, two optional R1-1-6, two optional R1-1-7, two optional R1-1-8 two optional R1-2-3, two optional R1-2-4, two optional R1-2-5, two optional R1-2-6, two optional R1-2-7 or two optional R1-2-8, together with the atoms to which they are attached, independently form “3- to 8-membered carbon ring”, “3- to 8-membered carbon ring” substituted with one or more R1-3-1, “3- to 8-membered heterocycle containing 1 to 3 heteroatoms independently selected from O, S and N”, “3- to 8-membered heterocycle containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more R1-3-2, C6-20 aromatic ring, C6-20 aromatic ring substituted with one or more R1-3-3, “5- to 12-membered heteroaromatic ring containing 1 to 4 heteroatoms independently selected from O, S and N”, “5- to 12-membered heteroaromatic containing 1 to 4 heteroatoms independently selected from O, S and N” substituted with one or more R1-3-4, C5-7 cyclic olefin, C5-7 cyclic olefin substituted with one or more R1-3-5, “5- to 7-membered hetero cyclic olefin containing 1 to 3 heteroatoms independently selected from O, S and N”, “5- to 7-membered hetero cyclic olefin containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more R1-3-6, provided that when multiple substituents are present, the substituents are the same or different;
R1-3-1, R1-3-2, R1-3-3, R1-3-4, R1-3-5 and R1-3-6 are independently oxo, hydroxyl, halogen, C1-6 alkyl, C1-6 alkyl substituted with one or more halogen, —OC1-6 alkyl, or, —OC1-6 alkyl substituted with one or more halogen; provided that when multiple substituents are present, the substituents are the same or different;
or, Ra-31 and Ra-32, Ra-51 and Ra-52, R1b1 and R1b2, R1d1 and R1d2, R11b1 and R11b2, R11d1 and R11d2, R11e1 and R11e2, Ra and Rb, Rc and Rd, R12c and R12d together with the nitrogen atom to which they are attached independently form “3- to 8-membered heterocycle containing 1 to 3 heteroatoms, wherein, one heteroatom is N, the other one or two heteroatoms independently selected from O, S and N”, or “3- to 8-membered heterocycle containing 1 to 3 heteroatoms, wherein, one heteroatom is N, the other one or two heteroatoms independently selected from O, S and N” substituted with one or more R1-4-1;
R1-4-1 is independently oxo, hydroxyl, halogen, C1-6 alkyl, C1-6 alkyl substituted with one or more halogen, —OC1-6 alkyl, or, —OC1-6 alkyl substituted with one or more halogen; provided that when multiple substituents are present, the substituents are the same or different;
A2 and A3 are independently CR2, R2 is hydrogen or halogen;
b is a single bond, both a and c are a double bond, A4 is N, A4 is NR5d,
R6 is independently “5-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N”, or, “5-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N” substituted with one or more R6-1;
R6-1 is halogen, hydroxyl, —CN, C1-6 alkyl, C1-6 alkyl substituted with one or more halogen, C1-6 alkyl substituted with one or more —OC1-6 alkyl, —OC1-6 alkyl, or, C1-6 alkyl —O— substituted with one or more halogen; provided that when multiple substituents are present, the substituents are the same or different;
R5d is

OG Complex Work Unit Chemistry
L1 is a bond, C1-6 alkylene or —C(═O)—;
Q1 is hydrogen, halogen, cyano, C2-6 alkenyl, C2-6 alkynyl, hydroxyl, —C(═O) R52a, —NR52b1R52b1, —C(═O)OR52c, —C(═O)NR52d1R52d2, C1-6 alkyl substituted with one or more halogen, C1-6 alkyl substituted with one or more hydroxyl, —OC1-6 alkyl, —OC1-6 alkyl substituted with one or more R5-1-1, C6-20 aryl, C6-20 aryl substituted with one or more R5-1-2, “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N”, “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N” substituted with one or more R5-1-3, C3-12 cycloalkyl, C3-12 cycloalkyl substituted with one or more R5-1-4, “4-to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N”, “4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more R5-1-5, C5-7 cycloalkenyl, C5-7 cycloalkenyl substituted with one or more R5-1-6, “5- to 7-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from O, S and N”, “5- to 7-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more R5-1-7; provided that when multiple substituents are present, the substituents are the same or different;
or, R1 and R5d, together with the atoms to which they are attached independently form “5- to 12-membered heterocyclic olefin containing 1 to 3 heteroatoms independently selected from O, S and N”;
R5-1-1, R5-1-2, R5-1-3, R5-1-4, R5-1-5, R5-1-6 and R5-1-7 are independently halogen, hydroxyl, oxo, cyano, C1-6 alkyl, C1-6 alkyl substituted with one or more halogen, C2-6 alkenyl, C2-6 alkynyl, —OC1-6 alkyl, —OC1-6 alkyl substituted with one or more halogen, —C(═O) R51a, —NR51b1R51b2, —C(═O)OR51c, or, —C(—O)NR51d1R51d2; provided that when multiple substituents are present, the substituents are the same or different;
R52a, R52b1, R52b, R52c, R52d1, R52d2, R51a, R51b1, R51b2, R51c, R51d1 and R51d2 are independently hydrogen, C1-6 alkyl, or, C1-6 alkyl substituted with one or more halogen;
or, R52b1 and R52b, R52d1 and R52d2, R51b1 and R51b2, R51d1 and R51d2, together with the nitrogen atom to which they are attached independently form “3- to 8-membered heterocycle containing 1 to 3 heteroatoms, wherein, one heteroatom is N, the other one or two heteroatoms independently selected from O, S and N”, or “3- to 8-membered heterocycle containing 1 to 3 heteroatoms, wherein, one heteroatom is N, the other one or two heteroatoms independently selected from O, S and N” substituted with one or more R1-5-1;
R1-5-1 is oxo, hydroxyl, halogen, C1-6 alkyl, C1-6 alkyl substituted with one or more halogen, —OC1-6 alkyl, —OC1-6 alkyl substituted with one or more halogen; provided that when multiple substituents are present, the substituents are the same or different.